Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Associations between frailty, physical performance, and renal biomarkers in older people with advanced chronic kidney disease.

PURPOSE: Impaired physical performance and frailty are common in older people with advanced chronic kidney disease but it is unclear which metabolic derangements contribute to these impairments. We, therefore, examined associations between renal biochemical markers and both physical performance and frailty in older people with advanced chronic kidney disease. METHODS: Secondary analysis of data from the BiCARB trial, which enrolled non-dialysing patients aged 60 and over, with chronic kidney disease stage 4/5, with serum bicarbonate < 22 mmol/L. Participants undertook the Short Physical Performance Battery, maximum grip strength and six-minute walk test at baseline, 3, 6, 12 and 24 months. Renal biochemistry (serum creatinine, cystatin C, phosphate, and bicarbonate), haemoglobin, 25-hydroxyvitamin D and NT-pro-B-type natriuretic peptide were measured at baseline. Associations between baseline renal biochemistry and physical performance, and between baseline biochemistry and the monthly rate of change in physical performance were assessed. RESULTS: We analysed data from 300 participants (mean age 74 years; 86 [29%] women). 148 (49%) were pre-frail, 86 (29%) were frail. In multivariable cross-sectional baseline analyses, only age and BMI were significantly associated with baseline short physical performance battery; age, sex, body mass index, NT-pro-BNP and 25-hydroxyvitamin D were significantly associated with baseline six-minute walk distance. No significant associations were found between biochemical markers and change in physical performance over time, except between baseline 25-hydroxyvitamin D concentration and change in six-minute walk distance. CONCLUSIONS: Biochemical markers associated with chronic kidney disease did not consistently associate with baseline physical performance or the rate of change of physical performance measures. TRIAL REGISTRATION: ISRCTN09486651.

Effect of allopurinol on phosphocreatine recovery and muscle function in older people with impaired physical function: a randomised controlled trial.

BACKGROUND: Allopurinol has vascular antioxidant effects and participates in purinergic signalling within muscle. We tested whether allopurinol could improve skeletal muscle energetics and physical function in older people with impaired physical performance. METHODS: We conducted a randomised, double blind, parallel group, placebo-controlled trial, comparing 20 weeks of allopurinol 600 mg once daily versus placebo. We recruited community-dwelling participants aged 65 and over with baseline 6-min walk distance of <400 m and no contraindications to magnetic resonance imaging scanning. Outcomes were measured at baseline and 20 weeks. The primary outcome was post-exercise phosphocreatine (PCr) recovery rate measured using 31P magnetic resonance spectroscopy of the calf. Secondary outcomes included 6-min walk distance, short physical performance battery (SPPB), lean body mass measured by bioimpedance, endothelial function and quality of life. RESULTS: In total, 124 participants were randomised, mean age 80 (SD 6) years. A total of 59 (48%) were female, baseline 6-min walk distance was 293 m (SD 80 m) and baseline SPPB was 8.5 (SD 2.0). Allopurinol did not significantly improve PCr recovery rate (treatment effect 0.10 units [95% CI, -0.07 to 0.27], P = 0.25). No significant changes were seen in endothelial function, quality of life, lean body mass or SPPB. Allopurinol improved 6-min walk distance (treatment effect 25 m [95% 4-46, P = 0.02]). This was more pronounced in those with high baseline oxidative stress and urate. CONCLUSION: Allopurinol improved 6-min walk distance but not PCr recovery rate in older people with impaired physical function. Antioxidant strategies to improve muscle function for older people may need to be targeted at subgroups with high baseline oxidative stress.

Temporal trends in anticholinergic medication prescription in older people: repeated cross-sectional analysis of population prescribing data.

BACKGROUND: in older people, medications with anticholinergic (antimuscarinic) effects are associated with adverse clinical outcomes, the risk increasing with increasing anticholinergic exposure. Many anticholinergics are recognised as potentially inappropriate and efforts to reduce prescription have been ongoing. We examined temporal trends of anticholinergic prescription and exposure in older people. METHODS: : anonymised data on all prescribed medication dispensed to people ≥65 years in Tayside, Scotland were obtained for the years 1995 (n = 67,608) and 2010 (n = 73,465). The Anticholinergic Risk Scale (ARS) was adapted (mARS) to include newer medications and medications identified in other scales as having moderate to strong anticholinergic activity. An individual's mARS score was the sum of scores for individual medications. Differences in prescription of anticholinergic medications and mARS scores between 1995 and 2010 were examined. RESULTS: : a significantly higher proportion of older people received any anticholinergic medication in 2010 compared with 1995 (23.7 versus 20.7%; P < 0.001). High anticholinergic exposure (mARS scores ≥3) was seen in 7.3% in 1995 and 9.9% in 2010 (P < 0.001). Prescription of individual anticholinergic medication was small-only three medications were prescribed to >2% of people. The risk of high anticholinergic exposure increased in those with polypharmacy, social deprivation, those living in care homes and women. CONCLUSION: : despite increasing evidence of adverse outcomes, the proportion of older people prescribed anticholinergic medications and the proportion with a high anticholinergic exposure has increased between 1995 and 2010. Prescription of individual drug is small so cumulative anticholinergic scores may help future efforts to reduce anticholinergic prescription in older people.